Methods of Producing Stabilized Solid Dosage Pharmaceutical Compositions Containing Morphinans

ABSTRACT

Methods for producing stabilized solid dosage form pharmaceutical compositions are provided. In particular, methods for preparing protected granules containing morphinans, and solid dosage form pharmaceutical compositions produced using the morphinan-protected granules are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.12/973,962, filed Dec. 21, 2010, which claims priority to U.S.Provisional Application No. 61/284,651 filed on Dec. 22, 2009, each ofwhich is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods of producing stabilized soliddosage forms of morphinan pharmaceutical compositions. In particular,the present invention relates to methods of preparingmorphinan-protected granules that may be incorporated into solid dosageforms of morphinan pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Minimizing the degradation of active pharmaceutical ingredients (APIs)in pharmaceutical compositions is an ongoing challenge in research anddevelopment. Degradation may occur from the physical or chemicalinstability of the API with incompatible pharmaceutical carriers in apharmaceutical composition, or by reactions of the API with headspaceoxygen or residual water in a composition.

Oxidation is a common mechanism of API degradation in pharmaceuticalcompositions. The process of oxidative degradation may occur via variousmechanisms such as autooxidation, nucleophilic addition, electrophilicaddition, or electron transfer. Regardless of the mechanism, degradantcompounds formed by the degradation of an API in a pharmaceuticalcomposition may impart potentially harmful properties to thecomposition.

If degradants are present in a pharmaceutical composition above thelevels prescribed by ICH Guidelines Q3A and Q3B, the degradants mustundergo a qualification procedure as part of the approval processrequired before the use and sale of the composition is allowed.Qualification of impurities typically involves costly studies usingmultiple animal models, and introduces considerable risk into thedevelopment process. If degradants of a pharmaceutical composition arefound to be carcinogenic or teratogenic, the composition will not gainFDA approval, diminishing the opportunity for commercialization of theAPI.

As a result, the process of selecting functional carriers for apharmaceutical composition is particularly challenging. A functionalpharmaceutical carrier is typically selected primarily to impart desiredperformance characteristics to the composition such as an extendedrelease profile. In addition, it is desirable to select functionalcarriers that are chemically compatible with the API in the composition.In certain compositions, it may be necessary to incorporate functionalcarriers that may be incompatible with the API in order to achieve adesired performance of the API in the body. In this situation,identifying an effective means to prevent the degradation of the API isan essential part of the development of a successful therapeuticcomposition.

For example, the formulation of a solid dosage form of an API mayincorporate a release-modifying pharmaceutical carrier in order toachieve a desired release profile after administration of the compound.Polymer carriers such as a polyethylene oxide (PEO) polymer may beincorporated into a pharmaceutical composition to impart an extendedrelease profile to the composition. PEO polymers are produced by aprocess of radical polymerization process followed by oxidativedegradation of the polymer to achieve the desired molecular weight. Theresulting PEO polymer carriers may retain residual peroxides and otheroxidative species from the production process that may cause theoxidation of the API molecules in any pharmaceutical composition thatincorporates PEO polymers. Typically, other excipients such asantioxidants or pH-lowering excipients may be incorporated into the APIcomposition to minimize the degradation of the API in the presence ofincompatible carriers such as PEO polymers in the pharmaceuticalcomposition. However, in a solid dosage form composition, this approachis less effective than in other dosage forms such as solutions orsuspensions.

Morphinans, a widespread class of analgesic APIs, are particularlyvulnerable to oxidative degradation, especially in compositions thatincorporate PEO polymer carriers or other pharmaceutical carriers thatcontain residual peroxides or other oxidative species. Because thephysiological effects of morphinans are notoriously sensitive to smallchanges in chemical structure, the formation of degradants may introduceundesirable properties to a pharmaceutical composition in which amorphinan is vulnerable to degradation. For solid dosage forms ofmorphinan compositions, the introduction of additional antioxidantexcipients or pH-lowering excipients to prevent the degradation of themorphinan, particularly when formulated in a solid dosage form, has beenrelatively ineffective to date.

A need exists in the art for a method of protecting an API fromdegradation in a solid dose form of a pharmaceutical composition. Inparticular, a need exists for a method of stabilizing morphinan APIs,which are especially vulnerable to oxidative degradation, in soliddosage forms of pharmaceutical compositions.

SUMMARY OF THE INVENTION

Briefly, therefore, one aspect of the disclosure provides a method forthe preparation of a solid dosage form pharmaceutical compositioncomprising a morphinan and at least one other active pharmaceuticalingredient. The method comprises three steps. In the first step, amixture comprising the morphinan and at least one excipient isgranulated in a manner such that the amount of morphinan exposed on thesurface of the granule is substantially reduced thereby forming amorphinan-protected granule. The second step comprises granulating amixture comprising the morphinan-protected granule, the activepharmaceutical agent, and at least one excipient to form a granulatedmixture. In the third step, the granulated mixture is blended with arelease-controlling polymer comprising a polyethylene oxide polymer toform the solid dosage form pharmaceutical composition comprising asustained release layer.

In another aspect of the disclosure, a method for the preparation of asolid dosage form pharmaceutical composition comprising oxycodone andacetaminophen is provided. The method comprises three steps. In thefirst step, a mixture comprising the oxycodone and at least oneexcipient is granulated in a manner such that the amount of oxycodoneexposed on the surface of the granule is substantially reduced therebyforming an oxycodone-protected granule. In the next step, a mixturecomprising the oxycodone-protected granule, the acetaminophen, and atleast one excipient is granulated to form a granulated mixture. Thethird step comprises blending the granulated mixture with arelease-controlling polymer comprising a polyethylene oxide polymer isgranulated to form the solid dosage form pharmaceutical compositioncomprising a sustained release layer.

An additional aspect of the disclosure provides a method for thepreparation of a bilayer tablet comprising a sustained release layer andan immediate release layer. The method comprises four steps. In a firststep, a mixture comprising oxycodone or hydrocodone and at least oneexcipient is granulated in a manner such that the amount of oxycodone orhydrocodone exposed on the surface of granule is substantially reducedthereby forming a morphinan-protected granule. In the next step, amixture comprising the morphinan-protected granule, the acetaminophen,and at least one excipient is granulated to form a granulated mixture.In the third step, the granulated mixture is blended with arelease-controlling polymer comprising a polyethylene oxide polymer toform a sustained release layer. In the final step, a mixture comprisingthe morphinan-protected granule from the first step is granulated withthe acetaminophen and at least one excipient to form the immediaterelease layer.

A further aspect of the disclosure encompasses a granule that issubstantially resistant to oxidative degradation of oxycodone. Thegranule comprises an interior region substantially comprising oxycodonethat is surrounded by an exterior region substantially comprising atleast one excipient. Moreover, the granule contains less than about 0.5%w/w of the total mass of oxycodone of a degradant selected from10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide afterbeing stored for 6 months at 40° C. and 75% relative humidity.

Another aspect of the disclosure provides a granule substantiallyresistant to oxidative degradation of hydrocodone. The granule comprisesan interior region substantially comprising hydrocodone that issurrounded by an exterior region substantially comprising at least oneexcipient, wherein the granule contains less than about 0.5% w/w of thetotal mass of hydrocodone of a degradant selected fromhydrocodone-n-oxide and hydrocodone aldol dimer after being stored for 6months at 40° C. and 75% relative humidity.

Yet another aspect of the disclosure provides a granule substantiallyresistant to oxidative degradation of a morphinan, the granule preparedby a process comprising granulating a mixture comprising the morphinanand at least one excipient in a manner such that the amount of morphinanexposed on the surface of the granule is substantially reduced therebyforming the morphinan-protected granule.

An additional aspect of the disclosure encompasses a pharmaceuticalcomposition comprising a plurality of oxycodone-containing granulessubstantially resistant to oxidative degradation of oxycodone and atleast one pharmaceutically acceptable carrier. The plurality of granulescomprise an interior region substantially comprising oxycodone that issurrounded by an exterior region substantially comprising at least oneexcipient, wherein the granule contains less than about 0.5% w/w of thetotal mass of oxycodone of a degradant selected from 10-hydroxyoxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after beingstored for 6 months at 40° C. and 75% relative humidity.

Another aspect of the disclosure provides a pharmaceutical compositioncomprising a plurality of hydrocodone-containing granules substantiallyresistant to oxidative degradation of hydrocodone and at least onepharmaceutically acceptable carrier. The plurality of granules comprisean interior region substantially comprising hydrocodone that issurrounded by an exterior region substantially comprising at least oneexcipient, wherein the granule contains less than about 0.5% w/w of thetotal mass of hydrocodone of a degradant selected from hydrocodonen-oxide and hydrocodone aldol dimer after being stored for 6 months at40° C. and 75% relative humidity.

Yet another aspect provides a solid dosage pharmaceutical compositioncomprising a plurality of oxycodone-protected granules andacetaminophen, the composition prepared by a process comprising (a)granulating a mixture comprising the oxycodone and at least oneexcipient in a manner such that the amount of oxycodone exposed on thesurface of the granule is substantially reduced thereby forming theplurality of oxycodone-protected granules; (b) granulating a mixturecomprising the plurality of oxycodone-protected granules, theacetaminophen, and at least one excipient to form a granulated mixture;and (c) blending the granulated mixture with a release-controllingpolymer comprising a polyethylene oxide polymer to form the solid dosageform the pharmaceutical composition comprising a sustained releaselayer.

Other features and iterations of the invention are described in moredetail below.

DETAILED DESCRIPTION

The invention provides methods of preparing morphinan-protected granulesby combining a morphinan with at least one excipient to form a mixture,and granulating the mixture. The resulting morphinan-protected granuleshave a physical structure that minimizes the amount of morphinan that isexposed on the surface of the granule. The morphinan-protected granulesmay stabilize the morphinan against various mechanisms of degradationsuch as oxidation by substantially decreasing the amount of morphinanexposed on the surface of the granule thereby reducing the degree ofcontact between the morphinan and the oxidative species in theenvironment surrounding the granules, including but not limited tocarriers and residual water in the composition, and atmospheric oxygenand moisture.

in addition, if chemically protective excipients including but notlimited to antioxidants and pH-adjusting agents are included in theexcipient mixture forming the morphinan-protected granule, the morphinancontained within the granule is further protected against degradation.Any oxidative species contained in the environment surrounding themorphinan-protected granules may react with the chemically protectiveexcipients situated the granules before they can reach the morphinan.

The morphinan-protected granules may be prepared using any device knownin the art, including but not limited to a high-shear wet granulator.The particular device used for granulation may affect the physicalproperties of the resulting granules, including but not limited togranule size, granule density, and granule porosity, all of which mayinfluence the protective properties of the granule against degradationof the morphinan. Regardless of the granulation method used to form thegranules, the distribution of morphinan and excipients within thegranules is influenced by at least several factors including but notlimited to the size of the morphinan particles relative to the excipientparticles in the mixture prior to granulation, the chemical propertiesof the morphinan and excipients including but not limited tohydrophobicity and ionic charge, and the presence of excipientsdissolved in the granulation solution used to prepare the granules.

The morphinan-protected granules prepared by the methods of theinvention may be incorporated into a solid dose form of a pharmaceuticalcomposition, including but not limited to tablet and capsuleformulations. In addition to protection against degradation, theinclusion of the morphinan in the form of granules imparts several otheradvantageous aspects to the resulting composition. Because the morphinanin the granules is protected, the choice of carrier may be selected tosatisfy constraints other than compatibility with the morphinan.Carriers in the composition may instead be selected based on factorsincluding but not limited to the cost of the carrier, the desirablemodified-release properties imparted by a particular carrier. Further,variation in the characteristics of the morphinan-protected granulesincluding granule size, excipients included in the granules, and thephysical structure of the granules may be used to control the releaseprofile or other pharmacokinetic characteristics of pharmaceuticalcompositions.

Detailed descriptions of various embodiments of the morphinan protectedgranules, methods of preparing the morphinan protected granules, andsolid dosage forms of pharmaceutical compositions that include themorphinan-protected granules are described in detail below.

(I) Morphinan-Protected Granules

The granules prepared by the methods of the invention stabilize themorphinan contained within the granules by substantially reducing theamount of morphinan exposed on the surface of the granule. In thisregard, significantly less of the morphinan is in contact with anyoxidative species in the environment outside of the granule, and mayadditionally provide chemical protection of the morphinan againstdegradation by surrounding the morphinan with chemically protectiveexcipients including but not limited to antioxidants that are containedwithin the morphinan-protected granule. The physical structure of themorphinan-protected granule may influence the protective efficacy of thegranule against degradation of the morphinan, and further influences thesuitability of the granules for inclusion in various solid dose forms ofpharmaceutical compositions, including but not limited to tablets andcapsules.

(a) Granule Structure

The physical structure of the granule includes the morphinan dispersedwithin the excipient mixture and granulated in a manner such that theamount of morphinan exposed on the surface of the granule issubstantially reduced. The particular physical structure of anyembodiment of a morphinan-protected granule is influenced by at leastseveral factors related to the method of preparing the granules and theparticular morphinan and excipients included in the granule. Theinfluence of these factors on the physical structure of the granules isdescribed in detail below.

In general, the physical structure of the granules may vary from anessentially random spatial distribution of the morphinan and excipientsthroughout the granules to a highly ordered distribution in whichessentially all of the morphinan is contained within a sharplydelineated interior region that is surrounded by an exterior region thatcontains essentially all of the excipients. In an embodiment, the amountof morphinan that is exposed at the surface of the granules is less thanabout 100% of the total weight of the morphinan in the granules. Inother embodiments, the amount of morphinan that is exposed at thesurface of the granules is less than about 95%, less than about 90%,less than about 80%, less than about 70%, less than about 60%, less thanabout 50%, less than about 40%, less than about 30%, less than about20%, less than about 10%, and less than about 5% of the total weight ofmorphinan in the granule.

Excipients contained within the granule may provide additionalprotection against degradation of the morphinan by chemicallyinteracting with degradative compounds surrounding or within thegranule. For example, the effectiveness of the excipients at protectingthe morphinans in the granule may be enhanced if at least one of theexcipients includes but is not limited to an antioxidant, a chelatingagent, or a pH-adjusting agent. Various embodiments of the excipientsincluded in the granule are described in detail below.

The density and porosity of the exterior regions of the granules mayinfluence the effectiveness of the exterior regions at protecting themorphinans in the granules from degradation. Exterior regions havinghigher densities and lower porosities may be more resistant topenetration by degradative compounds from outside the granule. Thedensities and porosities of the exterior regions of the granules may beinfluenced by at least several factors including but not limited to theparticular morphinan and excipients included in the granule and thedevice used to prepare the granule. For example, a granule preparedusing a high-shear wet granulator may have a higher density and lowerporosity compared to a granule with a similar composition prepared usinga fluid bed granulator.

The d₉₀ of the granules in various embodiments may be selected based onthe intended use of the granules, in particular the particular soliddosage form in which the granules are to be incorporated. The particulard₉₀ of the granule may be influenced by a variety of factors includingbut not limited to the composition of the granule and the granulationdevice used to prepare the granules. The d₉₀ of the granules may belarger for granule compositions having a higher proportion of excipientsincluding but not limited to binders and fillers relative to other typesof excipients.

In various embodiments, the granules may have an average d₉₀ of lessthan about 2000 μm. In other embodiments, the granules may have anaverage d₉₀ of less than about 1800 μm, less than about 1500 μm, lessthan about 1000 μm, less than about 900 μm, less than about 800 μm, lessthan about 700 μm, less than about 600 μm, less than about 500 μm, lessthan about 400 μm, less than about 300 μm, less than about 200 μm, lessthan about 150 μm, and less than about 100 μm. In one exemplaryembodiment in which the granules are to be incorporated in a soliddosage form including but not limited to a capsule, the granules may beless than about 1000 μm in average d₉₀. In another exemplary embodimentin which the granules are to be incorporated in a solid dosage formincluding but not limited to a tablet, the granules may be less thanabout 800 μm in average d₉₀. In yet another embodiment, the granules mayrange from about 150 μm to about 200 μm in average d₉₀.

(II) Granule Composition

The composition of the granules prepared using the methods of theinvention include a morphinan and at least one excipient. The particularcomposition of the granules may influence a variety of properties of thegranules including but not limited to the physical structure of thegranules, the stability of the morphinan contained within the granule,and the suitability of the granules for incorporation into a particulardry dosage form of a pharmaceutical composition.

One aspect of the composition that may influence the physical structureof the granules is the d₉₀ of the morphinan particles relative to thed₉₀ of the excipient particles in the mixture that used to form thegranules. As used herein, d₉₀ represents the particle diameter at which90% of the individual particles of a compound are smaller than thespecified diameter. Without being bound to any particular theory, when agranulation device including but not limited to a low-shear wetgranulator, a high-shear wet granulator, or a fluid bed granulator isused to granulate the mixture of the morphinan and at least oneexcipient, the compounds having a smaller d₉₀ relative to the othercompounds in the mixture tend to aggregate near the interior regions ofthe granules, and the compounds having larger d₉₀ tend to aggregate nearthe exterior regions of the granules, regardless of whether the compoundis a morphinan or an excipient.

As a practitioner skilled in the art may appreciate, for granulecompositions in which the morphinan accounts for an extremely lowproportion of the total mass of the granule, the size of the morphinanparticles relative to the excipient particles may not exert the sameinfluence on the physical structure of the resulting granules asdescribed previously. By way of a non-limiting example, if a granule isprepared using a mixture containing about 5% morphinan and about 95%excipients by weight, and the d₉₀ of the morphinan is larger than thed₉₀ of the excipients, the relative scarcity of the morphinan particlesmay result in a granule in which the individual morphinan particles aresurrounded by excipient particles, and the morphinan particles may belocated in both the interior region and the exterior region of thegranule.

In one embodiment, the d₉₀ of the morphinan is smaller than the d₉₀ ofthe excipients. In another embodiment, the d₉₀ of the morphinan is lessthan about 80% of the d₉₀ of the excipients. In yet other embodiments,the d₉₀ of the morphinan is less than about 75%, less than about 70%,less than about 65%, less than about 60%, less than about 55%, or lessthan about 50% of the d₉₀ of the excipients.

The d₉₀ values of the morphinan and the excipients may also beinfluenced by the capabilities of the particular device used to preparethe granules. Without being bound to any particular theory, when agranulation device including but not limited to a low-shear wetgranulator, a high-shear wet granulator, or a fluid bed granulator isused to granulate the mixture of the morphinan and at least oneexcipient, if the d₉₀ of a particular compound falls below a thresholdd₉₀, the particles of that compound tend to aggregate before they aregranulated, resulting in granules that have a non-homogenousdistribution of the compound from granule to granule.

In other embodiments, other properties of the morphinan and excipientsmay influence the physical structure of the granule including but notlimited to the hydrophobicity and ionic charge of the morphinan relativeto the one or more excipients. As a non-limiting illustrative example,if the morphinan is hydrophobic relative to the excipients and if apolar granulation fluid is used in the granulation process, hydrophobicrepulsive forces may tend to situate the morphinan within the interiorregion of the granules.

In one embodiment, the composition of the granules includes onemorphinan compound. In other embodiments, the composition of thegranules may further include one or more additional morphinan compoundswithin each granule. Any number of different morphinans may be includedin the composition of the granules, so long as all morphinans that areincluded in the granule are physically and chemically compatible.

An acid, as defined herein, refers to the acid and any pharmaceuticallyacceptable salt of the acid.

(a) Morphinans

The compositions of various embodiments of the granules include amorphinan. In one embodiment, the morphinan may be included in thegranules in an amount of up to about 90% of the total weight of thegranules. In other embodiments, the morphinan may be included in thegranules in an amount ranging up to about 80%, up to about 70%, up toabout 60%, up to about 50%, up to about 40%, up to about 30%, up toabout 20%, up to about 10%, up to about 1%, and up to about 0.5% of thetotal weight of the granules.

The morphinan included in various embodiments of the granules may beselected from opium, natural opium derivatives, semi-synthetic opiumderivatives, and synthetic opium derivatives. Non-limiting examples ofsuitable morphinans for various embodiments of the granules includeadulmine, allocryptopine, aporphine, benzylmorphine, berberine,bicuculine, bicucine, bulbocapnine, buprenorphine, butorphanol,canadine, capaurine, chelerythrine, chelidonine, coda mine, codeine,coptisine, coreximine, corlumine, corybulbine, corycavamine, corycavine,corydaline, corydine, corytuberine, cularine, cotamine, cryptopine,cycloartenol, cycloartenone, cyclolaudenol, dehydroreticuline,desomorphine, dextropropoxyphene, dextrorphanol, diacetylmorphine,dicentrine, dihydrosanguinarine, dipropanoylmorphine, epiporphyroxine,ethylmorphine, eupaverine, fagarine, fentanyl, glaucine,homochelidonoine, hydrocodone, hydrocotamine, hydromorphone,hydroxythebaine, isoboldine, isocorybulbine, isocorydine,isocorypalmine, isoquinoline, laudanidine, laudanine, laudanosine,levorphanol, magnoflorine, meconic acid, methadone, morphine,nalbuphine, nalmefene, naloxone, naltrexamine, α-naltrexol, β-naltrexol,naltrexone, naphthaphenanthridine, narceine, narceinone, narcotoline,narcotise, neopine, nicomorphine, norlaudanosoline, norsanguinarine,noscapine, opium, oripavine, oxycodone, oxymorphone, oxysanguinarine,palaudine; papaverine, papaveraldine, papaverrubine, perparin,pethidine, phenanthrene, phtalide-isoquinoline, porphyroxine, protopine,pseudocodeine, pseudomorphine, reticuline, salutaridine, sinoacutine,sanguinarine, scoulerine, somniferine, stepholidine, tapentadol,tetrahydroprotoberberine, thebaine, tramadol, and xanthaline. In anexemplary embodiment, the morphinan included in the granules may beselected from oxycodone, oxymorphone, hydrocodone, hydromorphone,nalbuphine, naloxone, buprenorphine, and naltrexone. In anotherexemplary embodiment, the morphinan in the granules is oxycodone orhydrocodone.

Any of the morphinans included in the embodiments of the granules mayhave a (−) or (+) orientation with respect to the rotation of polarizedlight, depending upon whether the starting substrate has (−) or (+)optical activity, and are referred to herein as (−)-morphinans and(+)-morphinans respectively. More specifically, each chiral center mayindependently have an R or an S configuration.

As an illustrative example, an embodiment of the granules may include amorphinan compound possessing a fused carbon ring structure. The ringatoms of the morphinan compound may be numbered as diagrammed in Formula(I) below. Morphinan compounds have asymmetric centers and the coremorphinan compound may have at least four chiral carbons including butnot limited to C-5, C-13, C-14, and C-9. In various embodiments, theconfiguration of the chiral carbons C-5, C-13, C-14, and C-9 may beRRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS,SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 carbonsare both oriented either on the alpha face or the beta face of themorphinan molecule.

In various embodiments of the granules, the morphinan may be provided inany solid form including but not limited to a finely divided solid, acrystal, a particle, a powder, or any other finely divided solid formknown in the art. Any finely divided solid form of the morphinan may beused so long as the d₉₀ of the morphinan particles are smaller than thed₉₀, of the one or more excipients as described above.

(b) Excipients

Various embodiments of the granules include one or more excipients inaddition to the morphinan. In general, the one or more excipients areselected to impart at least one or more desired physical or chemicalproperties to the granules, including but not limited to adhesion of theparticles of the morphinan and excipient compounds in the mixture tofacilitate the formation of granules, formation of physical barriersaround the morphinans in the granules, and chemical inhibition ofvarious mechanisms of degradation of the morphinans including but notlimited to oxidation. Non-limiting examples of the one or moreexcipients include binders, fillers, antioxidants, pH-adjusting agents,chelating agents, and antimicrobial agents.

In one embodiment, the one or more excipients may be introduced into themixture to be granulated in a solid form including but not limited to acrystal, a particle, a powder, or any other finely divided solid formknown in the art. In another embodiment, the one or more excipients maybe dissolved or suspended in a solvent and sprayed onto the mixture in agranulation device as a binder fluid during granulation.

(i) Binders

In general, binders are excipients included in various embodiments ofthe granule to impart structural integrity to the granules by bindingtogether the particles making up each granule. Non-limiting examples ofbinders suitable for the formulations of various embodiments includestarches, pregelatinized starches, gelatin, polyvinylpyrrolidone,cellulose, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone,polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol,polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, andcombinations thereof. The polypeptides may be any arrangement of aminoacids ranging from about 100 to about 300,000 Daltons.

In one embodiment, the binder may be introduced into the mixture to begranulated in a solid form including but not limited to a crystal, aparticle, a powder, or any other finely divided solid form known in theart. In another embodiment, the binder may be dissolved or suspended ina solvent and sprayed onto the mixture in a granulation device as abinder fluid during granulation.

(ii) Fillers

Fillers may be included in various embodiments of the granulecomposition as an excipient to increase the bulk volume of the granulesand to impart suitable compressibility characteristics to the granulesfor subsequent inclusion in solid dosage forms of pharmaceuticalcompositions including but not limited to tablets. Non-limiting examplesof fillers include carbohydrates, inorganic compounds, andpolyvinylpyrrolidone. Other non-limiting examples of fillers includedibasic calcium sulfate, tribasic calcium sulfate, starch, calciumcarbonate, magnesium carbonate, microcrystalline cellulose, dibasiccalcium phosphate, tribasic calcium phosphate, magnesium carbonate,magnesium oxide, calcium silicate, talc, modified starches, lactose,sucrose, mannitol, and sorbitol.

(iii) Antioxidants

Antioxidants are excipients included in various embodiments of thegranules to prevent the oxidation of the morphinan in the granules.Suitable antioxidants include, but are not limited to anoxorner,N-acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid,o-aminobenzoic acid, p-aminobenzoic acid (PABA), butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid,canthaxantin, alpha-carotene, beta-carotene, beta-caraotene,beta-apo-carotenoic acid, carnosol, carvacrol, catechins, chlorogenicacid, citric acid and its salts, clove extract, coffee bean extract,p-coumaric acid, 3,4-dihydroxybenzoic acid,N,N′-diphenyl-p-phenylenediamine (DPPD), dilauryl thiodipropionate,distearyl thiodipropionate, 2,6-di-tert-butylphenol, edetic acid,ellagic acid, erythorbic acid, sodium etythorbate, esculetin, esculin,6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethyl maltol,ethylenediaminetetraacetic acid (EDTA) and EDTA salts, eucalyptusextract, eugenol, ferulic acid, flavonoids (e.g., catechin, epicatechin,epigallocatechin (EGC), flavones (e.g., apigenin, chrysin, luteolin),flavonols (e.g., datiscetin, myricetin, daemfero), flavanones, fraxetin,fumaric acid, gallic acid, gentian extract, gluconic acid, glycine, gumguaiacum, hesperetin, alpha-hydroxybenzyl phosphinlc acid,hydroxycinammic acid, hydroxyglutaric acid, hydroquinone,N-hydroxysuccinic acid, hydroxytryrosol, hydroxyurea, rice bran extract,lactic acid and its salts, lecithin, lecithin citrate; R-alpha-lipoicacid, lutein, lycopene, malic acid, maltol, 5-methoxy tryptamine,monoglyceride citrate, monoisopropyl citrate; morin,beta-naphthoflavone, nordihydroguaiaretic acid (NDGA), oxalic acid,palmityl citrate, phenothiazine, phosphatidylcholine, phosphoric acid,phosphates, phytic acid, phytylubichromel, pimento extract,polyphosphates, quercetin, trans-resveratrol, rosemary extract,rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid,succinic acid, stearyl citrate, syringic acid, tartaric acid, thymol,tocopherols (i.e., alpha-, beta-, gamma- and delta-tocopherol),tocotrienols (i.e., alpha-, beta-, gamma- and delta-tocotrienols),tyrosol, vanilic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e.,lonox 100), 2,4-(tris-3′,5′-bi-tert-butyl-4′-hydroxybenzyl)-mesitylene(i.e., lonox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tertiarybutyl hydroquinone (TBHQ), thiodipropionic acid, trihydroxybutyrophenone, tryptamine, tyramine, uric acid, vitamin K and derivates,vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.

In another embodiment, an antioxidant agent may be subjected to aparticle size reduction process including but not limited to grinding,milling, sonication, or hammer milling in order to reduce the d₉₀ of theantioxidant agent to a value less than the d₉₀ of the morphinan (orother API included in the formulation) prior to granulation. In thisembodiment, the reduced d₉₀ of the antioxidant agent may result in adistribution of antioxidant agent that is clustered around the morphinanparticles, rather than near the outer surface of the granule. A granulehaving this physical structure may provide comparable protection of themorphinan in the granules against degradation as compared to granules inwhich the antioxidant agent is situated on the outside of the granuleusing a significantly lower amount of the antioxidant agent.

In an exemplary embodiment, the granule composition includes at leastone antioxidant including but not limited to citric acid and Na₂EDTA.

(iv) pH-Adjusting Agents

In various embodiments of the granule composition, a pH-adjusting agentmay be included as an excipient to raise or lower the pH of the granulein order to prevent the oxidation of the morphinan in the granules. Forexample, a pH-adjusting agent including but not limited to citric acidmay be incorporated into the composition granule in order to lower thepH of the granule. In this example, a lower pH prevents the oxidation ofthe granule by various oxidative compounds associated withrelease-modifying polymer incorporated into a sold dosage form,including but not limited to peroxides.

In another embodiment, a pH-adjusting agent may be subjected to aparticle size reduction process including but not limited to grinding,milling, sonication, or hammer milling in order to reduce the d₉₀ of thepH-adjusting agent to a value less than the d₉₀ of the morphinan priorto granulation. In this embodiment, the reduced d₉₀ of the pH-adjustingagent may result in a distribution of pH-adjusting agent that isclustered around the morphinan particles, rather than near the outersurface of the granule. Non-limiting examples of pH-adjusting agentsinclude citric acid, acetic acid, tartaric acid, malic acid, fumaricacid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodiumcarbonate and sodium bicarbonate.

(v) Chelating Agents

In various embodiments of the granule composition, a chelating agent maybe included as an excipient to immobilize oxidative species includingbut not limited to metal ions in order to inhibit the oxidativedegradation of the morphinan by these oxidative species. Non-limitingexamples of chelating agents include lysine, methionine, glycine,gluconate, polysaccharides, glutamate, aspartate, and Na₂EDTA.

(vi) Antimicrobial Agents

In various embodiments of the granule composition, an antimicrobialagent may be included as an excipient to minimize the degradation of themorphinan by microbial agents including but not limited to bacteria andfungi. Non limiting examples of antimicrobials include parabens,chlorobutanol, phenol, calcium propionate, sodium nitrate, sodiumnitrite, Na₂EDTA and sulfites including but not limited to sulfurdioxide, sodium bisulfite, and potassium hydrogen sulfite.

(III) Granule Stability

In various embodiments of the granule composition, the morphinan in thegranule is substantially resistant to degradation due to interactions ofthe morphinan with degradative compounds or conditions present in theenvironment or in the carriers surrounding the granules in a soliddosage form of a pharmaceutical composition. In one embodiment, themorphinan in the granules is substantially resistant to the formation ofdegradants resulting from a chemical change in the morphinan broughtabout during the production and/or storage of the pharmaceuticalcomposition containing the morphinan by the effect of factors includingbut not limited to light, temperature, pH, water, or reaction with anexcipient or carrier included in the pharmaceutical composition. Theparticular degradants formed in a pharmaceutical composition depend onthe particular morphinan and the at least one excipient within thegranule, as well as the particular carriers included in thepharmaceutical composition along with the granules.

Statutory requirements, including but not limited to ICH Guidelines Q3Aand Q3B identify maximum allowable amounts of degradants above which thedegradants must be reported and subjected to the qualification processdescribed above. According to ICH Guideline Q3B, the amount of anyindividual degradant must be reported if the amount of degradant exceeds0.10% of the total API weight for maximum daily doses of 1000 mg of APIor below. For APIs having average daily doses of above 1000 mg,degradants in excess of 0.05% of the total API mass must be reported.The ICH guidelines apply throughout the effective shelf life of thepharmaceutical composition.

Although no standardized method of assessing API stability exists atpresent, drug developers typically subject potential pharmaceuticalcompounds to periods of storage at accelerated degradation conditions,typically defined as a temperature of about 40° C. and a relativehumidity of about 75%. The period of storage time at the accelerateddegradation conditions may vary from about 1 day to about 6 months, butis typically about 6 months. In an embodiment, the formation of any onedegradant in the composition may be limited to less than about 0.5%,less than about 0.4%, less than about 0.3%, less than about 0.2%, lessthan about 0.1%, less than 0.05%, less than 0.04%, less than 0.03%, lessthan 0.02%, or less than 0.01% of the total mass of the morphinan afterabout two months of storage at a temperature of about 40° C. and arelative humidity of about 75%. In another embodiment, the formation ofany one degradant in the composition may be limited to less than about0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%,less than about 0.1%, less than 0.05%, less than 0.04%, less than 0.03%,less than 0.02%, or less than 0.01% of the total mass of the morphinanafter about six months of storage at a temperature of about 40° C. and arelative humidity of about 75%. In yet another embodiment, the formationof any one degradant in the composition may be limited to less thanabout 0.5%, less than about 04%, less than about 0.3%, less than about0.2%, less than about 0.1%, less than 0.05%, less than 0.04%, less than0.03%, less than 0.02%, or less than 0.01% of the total mass of themorphinan after about four weeks of storage at accelerated stabilityconditions at a temperature of about 40° C. and a relative humidity ofabout 75%.

In an exemplary embodiment, for a pharmaceutical compositionincorporating oxycodone as the morphinan and at least one excipient inthe form of granules, the granules contain less than about 0.5% w/w ofthe total mass of oxycodone of a degradant selected from 10-hydroxyoxycodone, di-hydroxy oxycodone, and oxycodone n-oxide after beingstored for 6 months at 40° C. and 75% relative humidity.

In another exemplary embodiment, for a pharmaceutical compositionincorporating oxycodone and at least one excipient in the form ofgranules, the granules contain less than about 0.5% w/w of the totalmass of oxycodone of each of one or more degradants selected from10-hydroxy oxycodone, di-hydroxy oxycodone, and oxycodone n-oxide afterbeing stored for 6 months at 40° C. and 75% relative humidity.

In another exemplary embodiment, for a pharmaceutical compositionincorporating hydrocodone as the morphinan and at least one excipient inthe form of granules, the granules contain less than about 0.5% w/w ofthe total mass of hydrocodone of a degradant selected from hydrocodonen-oxide and hydrocodone aldol dimer after being stored for 6 months at40° C. and 75% relative humidity. In another exemplary embodiment, for apharmaceutical composition incorporating hydrocodone and at least oneexcipient in the form of granules, the granules contain less than about0.5% w/w of the total mass of hydrocodone of each of one or moredegradants selected from hydrocodone n-oxide and hydrocodone aldol dimerafter being stored for 6 months at 40° C. and 75% relative humidity

(IV) Method of Preparing Granules

In various embodiments, the granules may be prepared by combining themorphinan with at least one excipient to form a mixture and granulatingthe mixture in a manner such that the amount of morphinan exposed on thesurface of the granules is minimized (thereby forming amorphinan-protected granule).

Suitable morphinans for the granule embodiments are described in detailin Section (IIa) above, and suitable excipients are described in Section(IIb) above. The mixture may be formed using any suitable method knownin the art including but not limited to stirring, shaking, vibrating,and blending. In an embodiment, the morphinan and dry excipients may becharged into a granulation device and mixed prior to the addition of thegranulation fluid.

Any suitable granulation device known in the art may be used to preparethe granules. As previously discussed, the particular granulation deviceselected for the preparation of the granules may influence the physicalproperties of the resulting granules. Non-limiting examples of suitabledevices for the preparation of the granules include a low-shear wetgranulator, a high-shear wet granulator, a fluid-bed granulator, aroller compactor, a vertical granulator, an oscillating granulator, agelatinizer, a pelletizer, and a spheronizer. The granulation device maybe selected in order to prepare granules having the desired granulephysical characteristics described in Section (II) above.

In an exemplary embodiment, a high-shear wet granulator is used toprepare the granules. The high-shear wet granulator may be capable ofpreparing granules having properties that enhance the protective effectof the granule, including but not limited to higher granule densitiesand lower granule porosities relative to granules prepared by otherdevices. Further, the high-shear wet granulator is capable of preparinggranules with a d₉₀ that is larger than other granulation devices,resulting in granules suitable for inclusion in a wider variety of soliddosage forms of morphinan compositions.

in the same exemplary embodiment, the morphinan and the excipients indry form of the composition are introduced into the wet high sheargranulator in order to form the mixture. After the morphinan and the dryexcipients are essentially homogeneously distributed within thegranulator, a granulation fluid is sprayed into the granulator. Invarious embodiments, the granulation fluid may be any volatile,non-toxic granulation fluid known in the art. Non-limiting examples ofsuitable granulation fluids include water, ethanol, isopropanol, andcombinations thereof. In other embodiments, one or more of theexcipients may be mixed with the granulation fluid prior to spraying thegranulation fluid into the granulator. In an exemplary embodiment, abinder including but not limited to pregelatinized starch may bedissolved into the granulation fluid including but not limited to waterto form a granulation solution, and the granulation solution may besprayed into the granulator in order to prepare the granules.

In an additional embodiment, the wet granules prepared in the high shearwet granulator may be dried using a drying device, resulting in driedgranules having a water content of less than about 5%, less than about4%, less than about 3%, or less than about 2% of the total weight of thegranules. Any suitable drying device known in the art may be used to drythe wet granules, including but not limited to an oven, a vacuum oven,and a rotary drum dryer.

(V) Solid Dosage Forms Incorporating Granules

The morphinan-protected granules prepared by various embodiments may beincorporated into various solid dosage pharmaceutical compositions.Non-limiting examples of solid dosage pharmaceutical compositionsincorporating embodiments of the morphinan granules include granules,tablets, and capsules. Non-limiting embodiments of tablets includeuncoated tablets, coated tablets, mini-tablets, orally disintegratingtablets, and bilayer tablets. Non-limiting embodiments of capsulesinclude hard capsules and multi-layer capsules. Depending on theselection of particular formulation, the solid dosage pharmaceuticalcomposition may have release characteristics including but not limitedto rapid release, sustained release, extended release, slow release,time release, and combinations thereof.

In an exemplary embodiment, solid dosage form pharmaceuticalcompositions are made via a two step process. First, themorphinan-protected granule is formed. The morphinan-protected granuleis then mixed with excipients and other active pharmaceuticalingredients, which are then granulated to form the solid dosage formpharmaceutical composition. The solid dosage form pharmaceuticalcomposition may include additional APIs. In an exemplary embodiment, thesolid dosage form pharmaceutical composition comprises a morphinan andacetaminophen. In additional embodiments, the solid dosage formpharmaceutical composition may comprise sustained release (SR) andimmediate release layers (IR). Typically, the SR and IR layers bothinclude the morphinan and acetaminophen. In each of the foregoingembodiments, the SR layer typically comprises a release-controllingpolymer comprising a polyethylene oxide polymer.

(a) Compositions of Solid Dosage Forms

Various embodiments of the solid dosage pharmaceutical compositionsincorporating the morph man-protected granules may include one or morepharmaceutically acceptable carriers in addition to the granules.Pharmaceutically acceptable carriers suitable for embodiments of thesolid dosage pharmaceutical compositions may include but are not limitedto binders, fillers, lubricants, diluents, non-effervescentdisintegrants, effervescent disintegrants, flavor-modifying agents,sweeteners, dispersants, coloring agents, taste masking agents,release-controlling polymers and combinations thereof.

(i) Binders

Non-limiting examples of binders suitable for the formulations ofvarious embodiments include starches, pregelatinized starches, gelatin,polyvinylpyrrolidone, cellulose, hydroxypropyl methylcellulose,hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone,polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol,polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, andcombinations thereof. The polypeptide may be any arrangement of aminoacids ranging from about 100 to about 300,000 Daltons.

(ii) Fillers

Non-limiting examples of fillers include carbohydrates, inorganiccompounds, and polyvinylpyrrolidone. Other non-limiting examples offillers include dibasic calcium sulfate, tribasic calcium sulfate,starch, calcium carbonate, magnesium carbonate, microcrystallinecellulose, dibasic calcium phosphate, tribasic calcium phosphate,magnesium carbonate, magnesium oxide, calcium silicate, talc, modifiedstarches, lactose, sucrose, mannitol, and sorbitol.

(iii) Lubricants

Non-limiting examples of lubricants include magnesium stearate, calciumstearate, zinc stearate, hydrogenated vegetable oils, sterotex,polyoxyethylene monostearate, talc, polyethylene glycol, sodiumbenzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and lightmineral oil.

(iv) Diluents

Diluents suitable for use include but are not limited topharmaceutically acceptable saccharides such as sucrose, dextrose,lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol;polyhydric alcohols; starches; pre-manufactured direct compressiondiluents; and mixtures of any of the foregoing.

(v) Non-Effervescent and Effervescent Disintegrants

Non-limiting examples of non-effervescent disintegrants include starchessuch as corn starch, potato starch, pregelatinized and modified starchesthereof, sweeteners, clays, such as bentonite, micro-crystallinecellulose, alginates, sodium starch glycolate, gums such as agar, guar,locust bean, karaya, pecitin, and tragacanth. Suitable effervescentdisintegrants include but are not limited to sodium bicarbonate incombination with citric acid, and sodium bicarbonate in combination withtartaric acid.

(vi) Flavor-Modifying Agents

Suitable flavor-modifying agents include but are not limited tosynthetic flavor oils and flavoring aromatics and/or natural oils,extracts from plants, leaves, flowers, fruits, and combinations thereof.Other non-limiting examples of flavor-modifying agents include cinnamonoils, oil of wintergreen, peppermint oils, clover oil, hay oil, aniseoil, eucalyptus, vanilla, citrus oils such as lemon oil, orange oil,grape and grapefruit oil, fruit essences including apple, peach, pear,strawberry, raspberry, cherry, plum, pineapple, and apricot.

(vii) Sweeten

Non-limiting examples of sweeteners include glucose (corn syrup),dextrose, invert sugar, fructose, and mixtures thereof (when not used asa carrier); saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevie rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,sylitol, hydrogenated starch hydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, particularlythe potassium salt (acesulfame-K), and sodium and calcium salts thereof.

(viii) Dispersants

Dispersants may include but are not limited to starch, alginic acid,polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified woodcellulose, sodium starch glycolate, isoamorphous silicate, andmicrocrystalline cellulose as high HLB emulsifier surfactants.

(ix) Coloring Agents

Suitable coloring agents include but are not limited to food, drug andcosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drugand cosmetic colors (Ext. D&C). These colors or dyes, along with theircorresponding lakes, and certain natural and derived colorants may besuitable for use in various embodiments.

(x) Taste-Masking Agents

Taste-masking agents include but are not limited to cellulosehydroxypropyl ethers (HPC) such as Klucel®, Nisswo HPC and PrimaFloHP22; low substituted hydroxypropyl ethers (L-HPC); cellulosehydroxypropyl methyl ethers (HPMC) such as Seppifilm-LC, Pharmacoat®,Metolose SR; Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and BenecelMP843; methylcellulose polymers such as Methocel® and Metolose®;Ethylcelluloses (EC) and mixtures thereof such as E461 Ethocel®,Aqualon®-EC, Surelease; Polyvinyl alcohol (PVA) such as Opadry AMB;hydroxyethylcelluloses such as Natrosol®; carboxymethylcelluloses andsalts of carboxymethylcelluloses (CMC) such as Aualon®-CMC; polyvinylalcohol and polyethylene glycol co-polymers such as Kollicoat IR®;monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols,modified food starch, acrylic polymers and mixtures of acrylic polymerswith cellulose ethers such as Eudragit® EPO. Eudragit® RD100, andEudragit® E100; cellulose acetate phthalate; sepifilms such as mixturesof HPMC and stearic acid, cyclodextrins, and mixtures of thesematerials. In other embodiments, additional taste-masking agentscontemplated are those described in U.S. Pat. Nos. 4,851,226, 5,075,114,and 5,876,759, each of which is hereby incorporated by reference in itsentirety.

(xi) Release-Controlling Polymers

Release-controlling polymers may be included in the various embodimentsof the solid dosage pharmaceutical compositions incorporating thegranules. In one embodiment, the release-controlling polymers may beused as a tablet coating. In other embodiments, including but notlimited to bilayer tablets, a release-controlling polymer may be mixedwith the granules and other excipients prior to the formation of atablet by a known process including but not limited to compression in atablet mold. Suitable release-controlling polymers include but are notlimited to hydrophilic polymers and hydrophobic polymers.

Suitable hydrophilic polymers include, but are not limited to, celluloseacetate, cellulose diacetate, cellulose triacetate, cellulose ethers,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, nitrocellulose, crosslinkedstarch, agar, casein, chitin, collagen, gelatin, maltose, mannitol,maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides,ammonia alginate, sodium alginate, calcium alginate, potassium alginate,propylene glycol alginate, alginate sodium carmellose, calciumcarmellose, carrageenan, fucoidan, furcellaran, arabicgum,carrageensgum, ghaftigum, guargum, karayagum, locust beangum, okragum,tragacanthgum, scleroglucangum, xanthangum, hypnea, laminaran, acrylicpolymers, acrylate polymers, carboxyvinyl polymers, copolymers of maleicanhydride and styrene, copolymers of maleic anhydride and ethylene,copolymers of maleic anhydride propylene or copolymers of maleicanhydride isobutylene), crosslinked polyvinyl alcohol and polyN-vinyl-2-pyrrolidone, diesters of polyglucan, polyacrylamides,polyacrylic acid, polyamides, polyethylene glycols, polyethylene oxides,poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol,polyvinyl chloride, polystyrenes, polyvinylpyrrolidone, anionic andcationic hydrogels, and combinations thereof.

Non-limiting examples of suitable hydrophobic polymers include celluloseacetate butyrate, cellulose acetate ethylcarbamate, cellulose acetateheptanoate, cellulose acetate methylcarbamate, cellulose acetateoctanoate, cellulose acetate phthalate, cellulose acetate propionate,cellulose acetate succinate, cellulose acetate trimaletate, celluloseacetaldehyde dimethyl acetate, cellulose butyrate, cellulosedimethylaminoacetate, cellulose disuccinate, cellulose dipalmitate,cellulose dicaprylate, cellulose propionate, cellulose propionatesuccinate, cellulose trioctanoate, cellulose tripropionate, cellulosetrimellitate, cellulose tripalmitate, cellulose trivalerate, cellulosevalerate palmitate, carboxymethyl cellulose, calcium carboxymethylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, ethylhydroxyethylcellulose, hydroxy propyl methylcellulose phthalate, methylcellulose, methyl ethyl cellulose, propyl cellulose, sodiumcarboxymethyl starch, polyvinyl acetate phthalate, polyvinyl alcoholphthalate, methacrylic acid copolymers, methacrylic acid estercopolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates,cyanoethyl methacrylate, aminoalkyl methacrylate copolymer,poly(acrylate), poly(methacrylate), poly(methyl methacrylate),poly(ethylacrylate), poly(ethyl methacrylate), poly(methacrylic acidanhydride), glycidyl methacrylate copolymers, ammonia methacrylatecopolymers, lecithins, aluminum monostearate, cetylalcohol, hydrogenatedbeef tallow, hydrogenated castor oil, hydrogenated vegetable oil,12-hydroxystearyl alcohol, glyceryl monopalmitate, glyceryl dipalmitate,glyceryl monostearate, glyceryl distearate, glyceryl tristearate,myristyl alcohol, stearic acid, stearyl alcohol, polyethyleneglycols,zein, shellac, bee's wax, carnauba wax, glyceryl behenate, Japan wax,paraffin, spermaceti, synthetic waxes, and combinations thereof.

(b) Methods of Producing Solid Dosage Forms

The solid dosage pharmaceutical compositions may be produced using anysuitable method known in the art. The particular production methodselected may depend on the desired type of solid dosage form and thedesired release profile.

(i) Production of Tablet Compositions

The pharmaceutical compositions in the form of a tablet may be producedusing any suitable method known in the art including but not limited todirect compression, wet granulation, dry granulation, and combinationsthereof. In one embodiment, the morphinan-protected granules may becombined with the one or more carriers and granulated into tabletgranules using any of the known granulation devices describedpreviously. In this same embodiment, the tablet granules formed from thecombination of the morphinan-protected granules and the one or morecarriers may be optionally blended with one or more additional carriersincluding but not limited to lubricants, and the resulting tablet blendmay be compressed into a tablet form. In another embodiment, one or morecarriers incorporated into the tablet granules may include arelease-controlling polymer to impart a modified release profile to theresulting tablet.

In yet another embodiment, a bilayer tablet may be formed by producing afirst tablet blend and a second tablet blend using a tablet granulationand blending process similar to those previously described. In thisembodiment, the first tablet blend may include a disintegrant in orderto impart a rapid release profile to the resulting tablet produced usingthe first tablet blend. The second tablet blend of this embodiment mayinclude a release-controlling polymer to impart a modified releaseprofile to the resulting tablet produced using the second tablet blend.The first tablet blend and the second tablet blend may be loaded into atableting device including but not limited to a bilayer tablet press,and pressed into a bilayer tablet in which the first layer may have arapid release profile and the second layer may have a modified releaseprofile.

In yet another embodiment, the morphinan-protected granules may becoated with a release-controlling polymer prior to incorporating themorphinan-protected granules into a solid tablet form in order to imparta modified release profile to the resulting tablet. In an additionalembodiment, the solid tablet form may be coated with arelease-controlling polymer to impart a modified release profile. Othercombinations of the embodiments described above may be used to produceadditional embodiments having a desired release profile or other desiredperformance characteristic including but not limited to masked taste,acceptable tongue-feel and mouth-feel, and enhanced stability.

(ii) Production of Capsule Compositions

The pharmaceutical compositions in the form of a capsule may be producedusing any suitable method known in the art including but not limited todirect loading into two-piece telescoping hard capsules. Non-limitingexamples of suitable hard capsules include hard starch capsules, hardgelatin capsules, and hard cellulose capsules. In one embodiment, thecapsule form of the pharmaceutical compositions may be produced byloading the morphinan-protected granules in to the hard capsule andsealing the capsule. In other embodiments, the morphinan-protectedgranules may be coated with a release-controlling polymer to impart amodified release profile to the hard capsule composition. In yet otherembodiments, a fraction of the morphinan-protected granules may becoated with a release-controlling polymer and combined with theremaining uncoated morphinan-protected granules prior to loading thegranules into the hard capsule.

(VI) Exemplary Embodiments

Exemplary embodiments of a granule and a solid dose pharmaceuticalcomposition are described below.

(a) Oxycodone-Protected Granule

An exemplary embodiment of a granule includes oxycodone,microcrystalline cellulose, pregelatinized starch, Na₂EDTA, and citricacid. The overall composition of the exemplary oxycodone-protectedgranule embodiment is listed in Table 10 below. In this embodiment, thegranules may be formed using the wet granulation method described inExample 5 below. In this embodiment, the oxycodone granules have agranule d₉₀ ranging from about 100 μm to about 400 μm, and contain lessthan about 2% water by weight.

(b) Bilayer Oxycodone/APAP Tablet

An exemplary embodiment of a solid dose pharmaceutical composition maybe a bilayer tablet that includes the oxycodone-protected granulesdescribed above. The exemplary bilayer tablet may be formed using themethod described in Example 2 below. The two layers of the bilayertablet in this embodiment include an instant-release (IR) layer and asustained release (SR) layer. The overall compositions of the IR layerand the sustained release layer of the exemplary bilayer tabletembodiment are listed in Table 1 below. The stability of the oxycodonein the exemplary bilayer tablet composition that incorporates oxycodonein a granular form is significantly better than a similar bilayer tabletcomposition that incorporates oxycodone in an unprotected powder form,as described in Example 2 below.

TABLE 1 Composition of Exemplary Oxycodone Bilayer Tablet CompositionDry Wt. (% total) Compound IR Layer SR Layer Protected oxycodonegranules 2.99% 2.62% APAP 77.73% 22.73% MCC 4.82% 26.81% Hydroxypropylcellulose 7.71% 1.34% Cross carmellose sodium 6.00% Silicon dioxide0.50% 0.5% Magnesium stearate 0.25% 1.0% Polyethylene oxide polymer45.0%

(c) Hydrocodone-Protected Granule

An exemplary embodiment of a granule includes hydrocodone,microcrystalline cellulose, pregelatinized starch. Na₂EDTA, and citricacid. The overall composition of the exemplary hydrocodone-protectedgranule embodiment is listed in Table 13 below. In this embodiment, thegranules may be formed using the wet granulation method described inExample 6 below. In this embodiment, the hydrocodone granules have agranule d₉₀ ranging from about 100 μm to about 400 μm after milling, andcontain less than about 5% water by weight.

(d) Bilayer Hydrocodone/APAP Tablet

An exemplary embodiment of a solid dose pharmaceutical composition maybe a bilayer tablet that includes the hydrocodone-protected granulesdescribed above. The exemplary bilayer tablet may be formed using themethod described in Example 2 below. The two layers of the bilayertablet in this embodiment include an instant-release (IR) layer and asustained release (SR) layer. The overall compositions of the IR layerand the sustained release layer of the exemplary bilayer tabletembodiment are listed in Table 2 below. The stability of the hydrocodonein the exemplary bilayer tablet composition that incorporateshydrocodone in a granular form is significantly better than a similarbilayer tablet composition that incorporates hydrocodone in anunprotected powder form.

TABLE 2 Composition of Exemplary Hydrocodone Bilayer Tablet CompositionDry Wt (% total) Compound IR Layer SR Layer Protected hydrocodonegranules 2.99% 2.62% APAP 77.73% 22.73% MCC 4.82% 26.81% Hydroxypropylcellulose 7.71% 1.34% Cross carmellose sodium 8.00% Silicon dioxide0.50% 0.5% Magnesium stearate 0.25% 1.0% Polyethylene oxide polymer45.0%

EXAMPLES

The following examples demonstrate various aspects of the invention.

Example 1 Incorporation of Protected Oxycodone Granules into BilayerTablet Composition

To demonstrate the feasibility of forming protected morphinan granulesand incorporating the protected morphinan granules into a solid dosageform, the following experiment was conducted.

Powdered oxycodone HCl, microcrystalline cellulose (MCC), and citricacid powder (an antioxidant) were mixed together and charged into ahigh-shear granulator. An aqueous solution containing pregelatinizedstarch (PGS) and Na₂EDTA (an antioxidant) was sprayed into thehigh-speed granulator, resulting in the formation of wet granules. Thewet granules were then dried until less than about 2% water remained inthe granules. The dried granules had particle sizes ranging from about100-300 μm. The composition of the protected oxycodone granules issummarized in Table 3:

TABLE 3 Composition of Protected Oxycodone Granules Dry Weight Compound(% tot. wt.) Oxycodone HCl 30.0% MCC 63.6% PGS 4.0% Na₂EDTA 0.4% Citricacid 2.0%

The oxycodone-protected granules were divided into two groups to beincorporated into batches of instant release (IR) granules and intobatches of sustained release (SR) granules used to form the IR and SRLayers of a bilayer tablet, respectively. Both the IR granules and theSR granules were formed using separate fluid bed granulation processes.In each process, the previously-formed protected oxycodone granules,powdered acetaminophen (APAP), and various excipients includingdisintegrants, binders; and fillers were charged into the fluid bedgranulation device and sprayed with a granulation fluid, resulting inthe formation of IR granules in one batch and SR granules in a secondbatch. The composition of the resulting IR and SR granules aresummarized in Table 4:

TABLE 4 Composition of IR and SR Granules Dry Wt (% total wt.) CompoundIR Layer SR Layer Protected oxycodone granules 16.1% 14.2% APAP 67.8%81.2% MCC 5.0% Hydroxypropyl cellulose 8.1% 4.5% Cross carmellose sodium3.0%

The IR granules were blended with lubricant excipients in preparationfor the tablet pressing process. Similarly, the SR particles wereblended with various excipients including lubricants, and polyethyleneoxide polymer, and a filler in preparation for the tablet pressingprocess. The compositions of the IR blend and the SR blend aresummarized in Table 5:

TABLE 5 Composition of IR and SR Blends Dry Wt. (% total wt.) CompoundIR Blend SR Blend IR granules 99.25% SR granules 52.30% Silicon dioxide0.50% 0.50% Magnesium stearate 0.25% 0.10% MCC 1.20% Polyethylene oxidepolymer 45.00%

The IR blend and the SR blend were loaded into a bilayer tablet pressand formed into bilayer tablets having about 29% of the IR blend andabout 71% the SR blend by weight.

The results of this experiment demonstrated that protected morphinangranules could be formed using a process of high shear wet granulationand incorporated into a solid oral therapeutic composition.

Example 2 Oxidative Stability Assessment of Bilayer Tablet Composition

To assess the effect of incorporating a morphinan in the form ofprotected granules into a solid dosage therapeutic composition on theoxidative stability of the composition, the following experiment wasconducted.

Unprotected bilayer tablets were formed using a process similar to thatdescribed in Example 1, except that powdered oxycodone HCl, rather thanprotected oxycodone granules, were incorporated into the IR and SRgranules formed using the fluid bed granulation device. Protectedbilayer tablets formed using protected oxycodone granules as describedin Example 1 were also obtained. The unprotected bilayer tablets weresimilar in composition to the protected bilayer tablets, except that theunprotected bilayer tablets lacked antioxidant excipients andoxycodone-protected granules, although the overall oxycodone contents ofthe two formulations of bilayer tablet were comparable.

A batch of protected bilayer tablets and a batch of unprotected tabletswere placed into an environmental chamber and exposed to acceleratedstability conditions. In particular, all bilayer tablets were kept inthe environmental chamber at a temperature of 55° C. and a relativehumidity of 80% for a period of six days. For the remainder of the firstmonth and for the duration of a second month, the bilayer tablets wereexposed to a temperature of 4° C. and a relative humidity of 75%.

After six days, one month, and two months in the environmental chamber,samples of the protected and unprotected formulations were removed fromthe chamber and submitted to mass spectrographic analysis to determinethe presence of three oxidative degradants of oxycodone: dihydroxyoxycodone, oxycodone n-oxide, and 10-hydroxy oxycodone. The results ofthese analyses are summarized in Table 6 below:

TABLE 6 Oxidative Stability of Unprotected vs. Protected Formulations ofBilayer Tablets Amount of Degradant Formed (% weight of oxycodone)Degradation Di-hydroxy 10-hydroxy Oxycodone n- Conditions oxycodoneoxycodone oxide Time Temp. Relative Not Not Not (days) (° C.) Humidity(%) Protected Protected Protected Protected Protected Protected 6 55 800.20 0.00 0.04 0.00 0.12 0.03 30 40 75 0.05 0.01 0.01 0.00 0.12 0.01 6040 75 0.11 0.02 0.03 0.00 0.21 0.03

The protected formulation of the bilayer tablets that incorporated theoxycodone-protected granules had significantly lower levels of alldegradants after exposure to all environmental conditions. No 10-hydroxyoxycodone was measured at any environmental condition for the protectedformulation of the bilayer tablet.

The results of this experiment demonstrated that the formation ofoxidative degradants of oxycodone was significantly inhibited by theincorporation of the oxycodone in the form of protected granules. Inparticular, the bilayer tablets formed using the protected oxycodonegranules were significantly more stable than similar bilayer tabletsformed using unprotected oxycodone powder.

Example 3 Effect of Granule Composition on Oxidative Stability

To assess the effect of various granule compositions on the oxidativestability of the morphinan encapsulated in the granules, the followingexperiment was conducted.

Granules containing oxycodone and various combinations of excipientswere formed using methods similar to those described in Example 1. Thespecific compositions of the granules are summarized in Table 7:

TABLE 7 Composition of IR and SR Granules Granule Composition (% w/w)Compound 1 2 3 5 6 Oxycodone 30 30 30 30 30 MCC 65 64.95 62.2 64.95 62.2HPC 5 4.6 4.6 BHA 0.05 0.05 EDTA 0.4 0.4 0.4 0.4 Ascorbic 2.8 2.8 AcidPGS 4.6 4.6

For granule compositions 1, 2, and 3 the HPC and EDTA were dissolved ina granulation solution and applied to a dry mixture of the remainingingredients. For granule compositions 5 and 6, the PGS and EDTA weredissolved in a granulations solution and applied to a dry mixture of theremaining ingredients.

The resulting granules were stored at accelerated stability conditionsfor a period of 4 weeks at 40° C. and 75% relative humidity. Samples ofthe granules were taken just before storage and after one, two, and fourweeks of storage at accelerated stability conditions and subjected tomass spectrographic analysis as described in Example 2 to determine thepresence of oxidative degradants of oxycodone. The results of theanalyses of the samples taken after four weeks of storage are summarizedin Table 8 below:

TABLE 8 Oxidative Stability of Granule Formulations Impurity After 4Weeks at Accelerated Degradation Conditions (% wt of oxycodone)Composition 6-a-Oxycodol Noroxy 1 0.11 0.01 2 0.11 0.02 3 0.33 0.13 50.11 0.00 6 0.29 0.14

The impurities for granule compositions 1, 2, and 5 were all ofcomparable low amounts, indicating that the granulation of the oxycodoneresulted in a protective effect from oxidative degradation. Thisprotective effect was achieved even in granule composition 1, which didnot include any antioxidant excipients. However, granule compositions 3and 6, which contained ascorbic acid, resulted in much higher levels ofoxidative impurities after 4 weeks of storage at accelerated stabilityconditions, indicating that the ascorbic acid may produce oxidativeproducts that result in the long-term degradation of the oxycodone.

The results of this experiment demonstrated the protective effect ofgranulation against the oxidative degradation of oxycodone, so long asascorbic acid was not included in the granule composition.

Example 4 Effect of Granulation Composition on Oxidative Stability ofSolid Dose Oxycodone/APAP Formulations

To assess the effect of encapsulation on the oxidative stability of themorphinan in various solid dose formulations, the following experimentwas conducted.

Solid dose tablets were formed using the methods described in Example 2.The solid dose tablets contained the oxycodone either in the protectedgranular form described in Example 3, or as the same ingredients in apowdered form rather than as granules. In both cases, the oxycodone andexcipients were combined with APAP and polyethylene oxide (PEO) polymer.Each tablet contained 10% of the oxycodone granule compositionsdescribed in Example 3, in either granulated or powdered form, 46.8%APAP, and 43.2% PEO polymer on a weight basis.

The protected and unprotected tablet formulations were stored ataccelerated stability conditions for a period of 4 weeks at 40° C. and75% relative humidity. Samples of the tablets were taken just beforestorage and after one, two, and four weeks of storage at acceleratedstability conditions and subjected to mass spectrographic analysis asdescribed in Example 2 to determine the presence of oxidative degradantsof oxycodone. The results of these analysis of the samples taken afterfour weeks of storage are summarized in Table 9 below:

TABLE 9 Effect of Granulation on Oxidative Stability of TabletFormulations Impurity After 4 Weeks at Accelerated CompositionDegradation Conditions (% wt of oxycodone) Combined 6-a-Oxycodol Noroxywith APAP and Protected Protected PEO Polymer granules UnprotectedGranules Unprotected 1 0.20 .74 0.03 .27 2 0.22 .51 0.05 .28 3 0.601.25* 0.11 .14* 5 0.17 .49 0.01 .18 *measured at two weeks after storage

All of the protected tablet formulations, in which the oxycodone wasgranulated using methods similar to those described in Example 1 formedsignificantly lower levels of impurities after storage for 4 weeks ataccelerated stability conditions compared to tablets containingnon-granulated oxycodone and the same excipients

The results of this experiment demonstrated that granulating theoxycodone and excipients prior to incorporating the granules in atableting process resulted in tablets with superior stability comparedto tablets formed using the same oxycodone and excipients in a loosepowder form, independent of the particular composition of excipients inthe formulation.

Example 5 Incorporation of Protected Hydrocodone Granules into BilayerTablet Composition

To demonstrate the feasibility of forming protected morphinan granulesand incorporating the protected morphinan granules into a solid dosageform, the following experiment was conducted to prepare a 7.5 mgoxycodone/325 mg acetaminophen tablet.

Powdered oxycodone HCl, microcrystalline cellulose (MCC), pregelatinizedstarch (PGS) and citric acid powder (an antioxidant) were mixed togetherand charged into a high-shear granulator. An aqueous solution containingpregelatinized starch (PGS) and Na₂EDTA (an antioxidant) was sprayedinto the high-speed granulator, resulting in the formation of wetgranules. The wet granules were then dried until less than about 5%water remained in the granules. The dried granules had particle sizesranging from about 100-300 μm after milling. The composition of theprotected hydrocodone granules is summarized in Table 10:

TABLE 10 Composition of Protected Oxycodone Granules Dry Weight Compound(% tot. wt.) Oxycodone HCl 30.0% MCC 63.6% PGS 4.0% Na₂EDTA 0.4% Citricacid 2.0%

The hydrocodone-protected granules were divided into two groups to beincorporated into batches of instant release (IR) granules and intobatches of sustained release (SR) granules used to form the IR and SRLayers of a bilayer tablet, respectively. Both the IR granules and theSR granules were formed using separate fluid bed granulation processes.In each process, the previously-formed protected hydrocodone granules,powdered acetaminophen (APAP), and various excipients includingdisintegrants, binders, and fillers were charged into the fluid bedgranulation device and sprayed with a granulation fluid, resulting inthe formation of IR granules in one batch and SR granules in a secondbatch. The composition of the resulting IR and SR granules aresummarized in Table 11:

TABLE 11 Composition of IR and SR Granules Dry Wt. (% total wt.) IR SRCompound Granules Granules Protected oxycodone granules 3.10% 9.79% APAP80.65% 84.81% MCC 5.0% Hydroxypropyl cellulose 8.0% 5.0% Crosscarmellose sodium 3.0% Silicon Dioxide 0.25% 0.4%

The IR granules were blended with lubricant excipients in preparationfor the tablet pressing process. Similarly, the SR particles wereblended with various excipients including lubricants, and polyethyleneoxide polymer, and a filler in preparation for the tablet pressingprocess. The compositions of the IR blend and the SR blend aresummarized in Table 12:

TABLE 12 Composition of IR and SR Blends Dry Wt. (% total wt.) CompoundIR Blend SR Blend IR granules 96.38% SR granules 26.80% CroscarmelloseSodium 3.11% Silicon dioxide 0.26% 0.39% Magnesium stearate 0.25% 1.0%MCC 26.81% Polyethylene oxide polymer 45.00%

The IR blend and the SR blend were loaded into a bilayer tablet pressand formed into bilayer tablets having about 23% of the IR blend andabout 77% the SR blend by weight.

The results of this experiment demonstrated that protected morphinangranules could be formed using a process of high shear wet granulationand incorporated into a solid oral therapeutic composition.

Example 6 Incorporation of Protected Hydrocodone Granules into BilayerTablet Composition

To demonstrate the feasibility of forming protected morphinan granulesand incorporating the protected morphinan granules into a solid dosageform, the following experiment was conducted to prepare a 7.5 mghydrocodone/325 mg acetaminophen tablet.

Powdered hydrocodone HCl, microcrystalline cellulose (MCC),pregelatinized starch (PGS) and citric acid powder (an antioxidant) weremixed together and charged into a high-shear granulator. An aqueoussolution containing pregelatinized starch (PGS) and Na₂EDTA (anantioxidant) was sprayed into the high-speed granulator, resulting inthe formation of wet granules. The wet granules were then dried untilless than about 5% water remained in the granules. The dried granuleshad particle sizes ranging from about 100-300 μm after milling. Thecomposition of the protected hydrocodone granules is summarized in Table13:

TABLE 13 Composition of Protected Hydrocodone Granules Dry WeightCompound (% tot. wt.) Hydrocodone HCl 30.0% MCC 63.6% PGS 4.0% Na₂EDTA0.4% Citric acid 2.0%

The hydrocodone-protected granules were divided into two groups to beincorporated into batches of instant release (IR) granules and intobatches of sustained release (SR) granules used to form the IR and SRLayers of a bilayer tablet, respectively. Both the IR granules and theSR granules were formed using separate fluid bed granulation processes.In each process, the previously-formed protected hydrocodone granules,powdered acetaminophen (APAP), and various excipients includingdisintegrants, binders, and fillers were charged into the fluid bedgranulation device and sprayed with a granulation fluid, resulting inthe formation of IR granules in one batch and SR granules in a secondbatch. The composition of the resulting IR and SR granules aresummarized in Table 14:

TABLE 14 Composition of IR and SR Granules Dry Wt. (% total wt.) IR SRCompound Granules Granules Protected hydrocodone granules 3.10% 9.79%APAP 80.65% 84.81% MCC 5.0% Hydroxypropyl cellulose 8.0% 5.0% Crosscarmellose sodium 3.0% Silicon Dioxide 0.25% 0.4%

The IR granules were blended with lubricant excipients in preparationfor the tablet pressing process. Similarly, the SR particles wereblended with various excipients including lubricants, and polyethyleneoxide polymer, and a filler in preparation for the tablet pressingprocess. The compositions of the IR blend and the SR blend aresummarized in Table 15:

TABLE 15 Composition of IR and SR Blends Dry Wt. (% total wt.) CompoundIR Blend SR Blend IR granules 96.38% SR granules 26.80% CroscarmelloseSodium 3.11% Silicon dioxide 0.26% 0.39% Magnesium stearate 0.25% 1.0%MCC 28.81% Polyethylene oxide polymer 45.00%

The IR blend and the SR blend were loaded into a bilayer tablet pressand formed into bilayer tablets having about 23% of the IR blend andabout 77% the SR blend by weight.

The results of this experiment demonstrated that protected morphinangranules could be formed using a process of high shear wet granulationand incorporated into a solid oral therapeutic composition.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible. Those of skill in the artshould, in light of the present disclosure, appreciate that many changescould be made in the specific embodiments that are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention, therefore all matter set forth is to beinterpreted as illustrative and not in a limiting sense.

1. A method for the preparation of a solid dosage form pharmaceuticalcomposition comprising a morphinan and acetaminophen, the methodcomprising: (a) granulating a first mixture comprising the morphinan andat least one excipient to form a plurality of morphinan-protectedgranules, wherein the morphinan in the morphinan protected-granules issubstantially resistant to oxidative degradation; (b) granulating asecond mixture in the presence of a granulation fluid, the secondmixture comprising the plurality of morphinan-protected granules,acetaminophen, and at least one excipient to form a plurality of tabletgranules; and (c) blending the plurality of tablet granules with arelease-controlling polymer comprising a polyethylene oxide polymer andoptionally at least one excipient to form the solid dosage formpharmaceutical composition comprising a sustained release layer.
 2. Themethod of claim 1, wherein the morphinan is chosen from adulmine,allocryptopine, aporphine, benzylmorphine, berberine, bicuculine,bicucine, bulbocapnine, buprenorphine, butorphanol, canadine, capaurine,chelerythrine, chelidonine, codamine, codeine, coptisine, coreximine,corlumine, corybulbine, corycavamine, corycavine, corydaline, corydine,corytuberine, cularine, cotamine, cryptopine, cycloartenol,cycloartenone, cyclolaudenol, dehydroreticuline, desomorphine,dextropropoxyphene, dextrorphanol, diacetylmorphine, dicentrine,dihydrosanguinarine, dipropanoylmorphine, epiporphyroxine,ethylmorphine, eupaverine, fagarine, fentanyl, glaucine,homochelidonoine, hydrocodone, hydrocotamine, hydromorphone,hydroxythebaine, isoboldine, isocorybulbine, isocorydine,isocorypalmine, isoquinoline, laudanidine, laudanine, laudanosine,levorphanol, magnoflorine, meconic acid, methadone, morphine,nalbuphine, nalmefene, naloxone, naltrexamine, α-naltrexol, β-naltrexol,naltrexone, naphthaphenanthridine, narceine, narceinone, narcotoline,narcotine, neopine, nicomorphine, norlaudanosoline, norsanguinarine,noscapine, opium, oripavine, oxycodone, oxymorphone, oxysanguinarine,palaudine, papaverine, papaveraldine, papaverrubine, perparin,pethidine, phenanthrene, phtalide-isoquinoline, porphyroxine, protopine,pseudocodeine, pseudomorphine, reticuline, salutaridine, sinoacutine,sanguinarine, scoulerine, somniferine, stepholidine, tapentadol,tetrahydroprotoberberine, thebaine, tramadol, and xanthaline.
 3. Themethod of claim 1, wherein the granulation in step (a) and (b) is doneusing a device chosen from a low-shear wet granulator, a high-shear wetgranulator, a fluid-bed granulator, a roller compactor, a verticalgranulator, an oscillating granulator, a gelatinizer, a pelletizer, aspheronizer, and combinations thereof.
 4. The method of claim 1, whereinthe excipient in step (a) or (b) is chosen from a binder, a filler, anantioxidant, a pH-adjusting agent, a chelating agent, an antimicrobialagent and combinations of any of the foregoing excipients.
 5. The methodof claim 1, wherein the solid dosage form pharmaceutical composition ischosen from granules, uncoated tablets, coated tablets, mini-tablets,bilayer tablets, orally disintegrating tablets, hard capsules, andmultilayer capsules.
 6. The method of claim 1, wherein the methodfurther comprises (d) granulating a third mixture comprising theplurality of morphinan-protected granules, the acetaminophen, and atleast one excipient to form a plurality of immediate release granules.7. The method of claim 6 wherein the method further comprises: (e)blending the immediate release granules with at least one excipient toform the immediate release layer.
 8. The method of claim 1, wherein themorphinan is hydrocodone.
 9. The method of claim 1, wherein themorphinan is oxycodone.
 10. A granule substantially resistant tooxidative degradation of a morphinan selected from the group consistingof oxycodone and hydrocodone the granule comprising an interior regionsubstantially comprising the morphinan and an exterior regionsubstantially comprising at least one excipient chosen from a binder, afiller, an antioxidant, a chelating agent, and combinations thereof,wherein the exterior region surrounds the interior region and whereinthe granule contains less than about 0.5% w/w of the total mass of adegradant after being stored for 6 months at 40° C. and 75% relativehumidity.
 11. The granule of claim 10, wherein less than about 20% ofthe total weight of the morphinan in the granule is exposed on thesurface of the granule.
 12. The granule of claim 10, further comprisingat least one additional active pharmaceutical ingredient.
 13. Thegranule of claim 12, wherein the at least one additional activepharmaceutical ingredient is acetaminophen.
 14. A solid dosagepharmaceutical composition comprising a plurality of morphinan-protectedgranules and acetaminophen, the composition prepared by a processcomprising: (a) granulating a first mixture comprising the morphinan andat least one excipient to form the plurality of morphinan-protectedgranules, wherein the morphinan in the morphinan-protected granules issubstantially resistant to oxidative degradation; (b) granulating asecond mixture in the presence of a granulation fluid, the secondmixture comprising the plurality of morphinan-protected granules, theacetaminophen, and at least one additional excipient to form a pluralityof tablet granules; and (c) blending the plurality of tablet granuleswith a release-controlling polymer and optionally at least one carrierto form the solid dosage pharmaceutical composition comprising asustained release layer.
 15. The solid dosage pharmaceutical compositionof claim 14, further comprising step (d) which includes granulating athird mixture in the presence of a granulation fluid, the third mixturecomprising morphinan-protected granules, acetaminophen, and at least oneadditional excipient to form a plurality of immediate release granules,and step (e) blending the immediate release granules with at least oneexcipient to form an immediate release layer.
 16. The solid dosagepharmaceutical composition of claim 14, wherein less than about 30% ofthe total weight of the morphinan in the tablet-protected granules isexposed on the surface of the granules.
 17. The solid dosagepharmaceutical composition of claim 14, wherein the at least onepharmaceutically acceptable carrier is incompatible with the morphinan.18. The solid dosage pharmaceutical composition of claim 14, wherein themorphinan is oxycodone and the degradant is selected from 10-hydroxyoxycodone, di-hydroxy oxycodone, and oxycodone n-oxide.
 19. The soliddosage pharmaceutical composition of claim 14, wherein the morphinan ishydrocodone and the degradant is selected from hydrocodone-n-oxide andhydrocodone aldol dimer.
 20. The solid dosage pharmaceutical compositionof claim 14, wherein the release-controlling polymer is a hydrophilicpolymer.
 21. The solid dosage pharmaceutical composition of claim 14,wherein the hydrophilic polymer is a polyethylene oxide.